SGC STIMULATORS OR SGC ACTIVATORS AND PDE5 INHIBITORS IN COMBINATION WITH ADDITIONAL TREATMENT FOR THE THERAPY OF CYSTIC FIBROSIS

摘要

The present invention relates to soluble guanylate cyclase (sGC) and to phosphodiesterases (PDEs) and the pharmacology of sGC stimulators, sGC activators and PDE inhibitors (PDE5i) in combination with a) treatments, leading to increased cGMP mobilization, and/or b) tretaments correcting and/or potentiatiating CFTR function, and/or c) treatments currently used as standard of care in Cystic Fibrosis, and/or d) antinflammatory treatments for the preparation of medicaments for the treatment of Cystic Fibrosis (CF) with improved efficacy over methods of treatments already known.

主权项

1. Combination of at least one sGC stimulator or activator selected from the group comprising 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidinamine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-{4,6-diamino-2-[5-fluor-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (3a), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl-carbamate (4), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorbenzyl)1H-pyrazolo[3,4-b]pyridine (4a), 5-chloro-2-(5-chlorothiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (6), 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (7), and/or 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid (5), 1-{6-[5-chloro-2-({4-trans-4-}trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (8), 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid (9), 1[6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-1H-pyrazole-4-caboxylic acid (10), 1-({2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (11), 4-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)benzoic acid (12), 1-({2-[2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (13) with a PDE5 inhibitor selected form the group comprising Vardenafil, Sildenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil, Lodenafil, UK 369.003, UK 371.800, SLx2101 and LAS34179- and at least one other pharmacological compound selected from the group of Nitrates, NO-Donors, Natriumnitroprussid, Nitro-glycerine, Isosorbidmononitrate, Isosorbiddinitrate, Molsidomin or SIN-1, inhaled Nitric Oxide or VX-809, VX-707, VX-661 or systemic or nebulized antibiotics, Dornase Alpha (rhDNase), hypertonic saline, asthma treatments or systemic or nebulized glucocorticoids, serine protease inhibitors, elastase inhibitors.